EP2935199B1 - Esters d'acide glycyrrhétinique, leur préparation et leurs applications cosmétiques - Google Patents

Esters d'acide glycyrrhétinique, leur préparation et leurs applications cosmétiques Download PDF

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EP2935199B1
EP2935199B1 EP13828837.8A EP13828837A EP2935199B1 EP 2935199 B1 EP2935199 B1 EP 2935199B1 EP 13828837 A EP13828837 A EP 13828837A EP 2935199 B1 EP2935199 B1 EP 2935199B1
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ester
polyglycerol
formula
glycyrrhetinic acid
acid
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EP2935199A1 (fr
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Giammaria Giuliani
Anna Benedusi
Guido BREGAGLIO
Antonio Mascolo
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Giuliani SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • A61Q1/14—Preparations for removing make-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/005—Preparations for sensitive skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/02—Preparations for cleaning the hair

Definitions

  • the present invention relates to esters of glycyrrhetinic acid with polyglycerolsorbitol and their applications in the cosmetic field.
  • the process of skin ageing consists in the natural evolution of structure and tissues affecting this organ which takes place since the embryonic period and continues until an old age.
  • ROS reactive oxygen species
  • the derivatives of liquorice root have long been used as lenitive substances in preparation for skin use and there are various conditions for which the topical application of these substances is advantageous, an example being the treatment of eczema, allergic and contact dermatitis and the treatment of psoriasis.
  • 18-Beta glycyrrhetinic acid is a pentacyclic triterpenoid which is obtained by hydrolysing glycyrrhizic acid, triterpenic saponin, naturally present in the root and rhizome of Glychyrrhiza Glabra.
  • glycyrrhetinic acid originating from the hydrolysis of glycyrrhizic acid is a part of the molecule having lenitive activity:
  • 18-beta glycyrrhetinic acid is in the form of a white, odourless powder, insoluble in water and oils, while it is soluble in ethanol.
  • percutaneous absorption which from the quantitative point of view may be defined as the amount of a certain substance that may be found at a systemic level within a certain time interval after application onto the skin.
  • the active ingredient vice versa has to obtaining the highest local effectiveness with the lowest systemic absorption.
  • Molecules having a high molecular weight generally are not capable of penetrating into the deepest layers. If not susceptible to hydrolysis, their are bound to remain on the surface.
  • EP1468696 discloses anti-inflammatory pharmaceutical compositions containing glyceryl glycyrrhetinate.
  • the inventors have found that by conveniently modifying an ester of glycyrrhetinic acid it is possible to increase the solubility of glycyrrhetinic acid increasing the possibilities of use of this substance in the cosmetic field.
  • the present invention provides an ester of glycyrrhetinic acid having formula (I): where
  • the present invention is directed to a cosmetic composition
  • a cosmetic composition comprising at least one ester of glycyrrhetinic acid having formula (I) and at least a cosmetically acceptable carrier.
  • the present invention relates to the process for manufacturing such ester of glycyrrhetinic acid having formula (I).
  • the present invention relates to the use of said ester of glycyrrhetinic acid having formula (I) or of said cosmetic composition as an anti-ageing agent in the topical treatment of the skin, particularly sensitive skin.
  • the present invention therefore relates to an ester of the glycyrrhetinic acid having formula (I): where
  • polyglycerol means the products of condensation between molecules of glycerol, that is dimers, trimers, oligomers and polymers of glycerol.
  • the simplest example is diglycerol or diglycerin which is obtained by condensing two molecules of glycerol.
  • the dehydration reaction may involve all three hydroxyl groups of the molecule and therefore may have condensations of the alpha-alpha type( ⁇ - ⁇ , that is between two hydroxyls bound to primary carbon atoms of two molecules of glycerol), beta-beta ( ⁇ - ⁇ , that is between two hydroxyls bound to secondary carbon atoms of two molecules of glycerol) and alpha-beta ( ⁇ - ⁇ , that is between one hydroxyl bound to a primary carbon atom of a molecule of glycerol and one hydroxyl bound to a secondary carbon atom of another molecule of glycerol) type, as in the structures reported below:
  • the moieties of glycerol and oligomers thereof containing up to 10 units of monomer have been found to be particularly preferred; in fact, an increase in the degree of polymerization of polyglycerols corresponds to a decrease in their purity, together with the presence of an increasing number of moieties having a different molecular weight, which make the chemical-physical properties of the final polyesters less and less homogeneous. Furthermore, it should be noted that with an increase in the degree of polymerization, and thus in the molecular weight, an increase in the viscosity and a reduction of hygroscopy of the molecule are observed.
  • polyglycerols may be synthesized by resorting to methods providing for the condensation of glycerol with alkaline catalysis (dehydration thereof) with water elimination.
  • the result of this synthesis normally is a mixture of oligomers which may comprise unreacted glycerol, cyclic products and very high oligomers.
  • Conditions of temperature, typically above 200°C, synthesis duration and vacuum favour the formation of the desired structures.
  • Polygly indicates a moiety of polyglycerol having a degree of polymerization from 1.5 to 10, more preferably indicates a moiety of polyglycerol having a degree of polymerization from 3 to 5.
  • polyglycerol (polygly) having formula (I) contains 2 to 10 units of glycerol, preferably 2 or three units of (poly)glycerol.
  • Polygly is a moiety of polyglycerol-3, more preferably the trimer wherein the three units of glycerol are bound to each other in a configuration ⁇ - ⁇ :
  • the moiety of sorbitol, that is Sorb, is present in the ester of the invention in a number from 1 to 3, preferably, the ester of the invention comprises only one moiety of sorbitol, n is 1.
  • the ester of the present invention comprises a moiety of polyglycerol-3, wherein the three units of glycerol are bound to each other in a configuration ⁇ - ⁇ , and a moiety of sorbitol, having formula (Ia):
  • ester of the invention has the following formulae:
  • the present invention relates to a process for preparing the ester of glycyrrhetinic acid having formula (I), comprising the steps of:
  • glycerol or polyglycerol may be used pure or in a mixture thereof.
  • glycerol or polyglycerol in a pure form are used.
  • Step ii) of esterification may be catalyzed by acids or bases.
  • an acid catalyst is used, for example paratoluenesulfonic acid or methanesulfonic acid, or no added catalyst, in this case taking advantage of the acidity of glycyrrhetinic acid itself.
  • the laboratory synthesis may be carried out using different equipment.
  • a glass spherical reactor (flask) placed inside a microwave oven may be used, provided with an anchor mixer, a contact thermometer, a nitrogen suction pipe, a Claisen distiller complemented on top by a Graham distiller and in the last neck an addition funnel.
  • a reactor consisting of a two-necked pyrex glass flask placed inside a laboratory electrical oven and connected to a three-necked glass candlestick, which allows the passage of the metal bar for mechanically stirring the product (central bar) and circulating a nitrogen flow.
  • the reaction temperatures are variable and may be from 145°C to 180°C in case of a synthesis in a microwave oven, and from 130°C to 220°C in case of a synthesis in an electrical oven.
  • glycerol or oligomers thereof and glycyrrhetinic acid are used or a slight excess of glycerol or polyglycerol is fed, for example 5-10%.
  • the invention relates to an ester having formula (I) obtainable by the process of synthesis described above.
  • the characterization of the ester having formula (I) of the invention may be made through chromatographic means, in particular through the SEC technique (Size Exclusion Chromatography).
  • SEC Size Exclusion Chromatography
  • chromatograms are obtained that report peaks, corresponding to a substance or fraction exiting from the instrument, as a function of time; after having calibrated the instrument with reference compounds, conveniently having hydrodynamic volume similar to that of molecules or polymer to be detected; for example a polystyrene having a known molecular weight, the technique provides among others the values:
  • the invention is related to cosmetic compositions, in particular compositions for topical use, comprising at least one ester of glycyrrhetinic acid having formula (I) and at least a cosmetically acceptable carrier.
  • Cosmetically acceptable carriers suitable for the composition of the invention may be ingredients selected from rheology modifiers, plasticizers, emulsifiers, surfactants, wetting agents, refratting agents, solubilizing agents, colorants, lubricants, stabilizers, conditioning agents, fragrances, essential oils, adsorbents, preservatives, buffering agents, antimicrobial agents, antioxidants, antiseborrhoeic agents, antistatic agents, absorbent agents, chemical or physical solar filters, astringents, chelating agents, skin conditioning agents, covering agents, denaturant agents, depigmenting agents, emollients, emulsifying agents, non filmogenic agents, moisturising agents, hydrotrope agents, lenitive agents, smoothing agents, matting or pearly
  • compositions for topical use of the invention may be for rinsing or not and have properties suitable for applications in the cosmetic and dermatological field.
  • At least one ester of glycyrrhetinic acid having formula (I) is present in the cosmetic composition of the invention in amounts from 0,01 to 20% by weight, preferably from 0.05 to 5% by weight on the composition weight.
  • the cosmetic composition of the invention may be in any forms suitable for local or topic application.
  • composition of the invention may be in liquid form for example as a lotion, solution, suspension, shampoo, milk or in a solid or semi-solid or fluid form for example as a conditioner, serum, ointment or cream.
  • the composition of the invention is in a liquid form for example in form of a water based lotion containing one or more carriers and/or excipients suitable for cosmetic applications.
  • the composition may generally contain water from about 1 to 99.9% by weight. In some embodiments, water is present in amounts from 5 to 95% by weight. In other embodiments, water is present in amounts from 10 to 90% by weight.
  • the cosmetic composition is anhydrous or it contains an amount of water less than 10% by weight.
  • the cosmetically acceptable carrier is anhydrous or containing an amount of water less than 2% by weight, confined within a soft gelatin capsule.
  • the carrier of the composition of the invention is a base preparation for cosmetic formulations, preferably for fluid preparations formulation suitable for skin application.
  • composition of the invention may be applied, in a effective amount, directly onto the portion to be treated, typically face or body skin or on the scalp.
  • the composition of the invention has the following formulations, where the concentration of each component is expressed in % by weight on the overall weight of the composition: Formulation 1 - MOISTURIZING SERUM Component Concentration w/w (%) Ammonium acryloyldimethyltaurate VP copolymer 0,10-1,50 Potassium sorbate 0.01 - 0.10 Sodium Benzoate 0.01 - 0.10 Pentylene glycol 0.50 - 4.00 Ester having formula (I) 0.05 - 1.00 Propanediol 0.50 - 8.00 Sodium hydroxide 0.005-0.20 Citric acid q.s.
  • a method for cosmetic treatment comprising the local application of an effective amount of a cosmetic application of the type described above.
  • the cosmetic compositions of the invention offer advantages compared to cosmetic or dermatological use of glycyrrhetinic acid as such or cosmetic compositions which contain it as will be apparent from the following Examples.
  • Glycerol or polyglycerol are safe substances to be used and are able to form polymeric structures very different among them, linear, branched and iper-branched with better features of solubility and cytotoxicity compared to polyethilenic glycol polymers (used in known compositions).
  • compositions properties that contain it being these properties of the chemical physical type, for example solubility or absorption kinetics of the active ingredient, up to the realization of modified release forms of the glycyrrhetinic acid regulated by a chemical mechanism, due to the fact that the ester linkage, in certain conditions, can be susceptible towards hydrolysis or enzymatic cleavage in situ.
  • the ester of the invention due to the presence of a number of hydroxyl groups able to form hydrogen bridges with as many water molecules, behaves as a multifunction reservoir for glycyrrhetinic acid, able to normalize and moisture the skin in depth.
  • the ester of the invention is particularly advantageous, in the light of greater tolerability compared to glycyrrhetinic acid, in order to produce a sebum-normalizing action for the skin.
  • the androgen hormones concentration is the most important regulatory factor of the sebum secretion; in particular, the 5-alpha reductase enzyme converts 4-androstenedione into dihydrotestosterone, a metabolite able to significantly increase the sebaceous secretion.
  • a further advantage obtained with the cosmetic use of the ester of the invention is related to the antimicrobial action of glycyrrhetinic acid which produces an overall reduction of lipase activity of bacterial origin, associated to a lower production of free fat acids which determines a sebum-normalizing action towards skin.
  • polyglycerol purity it has to be noted that commercial products used may also contain monomers and oligomers with lower and higher polymerization level.
  • Polyglycerol-3 may contain up to 15 of glycerol as well as polyglycerols with higher molecular weight.
  • 240 g of polyglycerol-3 have been placed in a glass spherical reactor (flask) placed inside a microwave oven.
  • the flask is provided with an anchor mixer, a contact thermometer, a nitrogen suction pipe, a Claisen distiller complemented on top by a Graham distiller and in the last neck an addition funnel.
  • both heating and a slow stirring were activated. Once the temperature of 90/95°C was reached, the system was placed under a very light stream of nitrogen.
  • reaction mixture was placed under high vacuum and 260 g of sorbitol (70% solution) dripped into the flask.
  • reaction water started at about 146°C. During about 80 minutes, about 20% of the total reaction water was distilled. At this point, the course of esterification was followed by determining the acidity index (indicator: phenolphthalein).
  • the system was cooled down at 80°C and the reactor discharged.
  • reaction water was significantly reduced when the product reached about 160°C.
  • duration of laboratory reaction was of about 3 hours. A dense product, slightly amber-coloured and nearly odourless was obtained.
  • hypophosphorous acid could be added in order to protect the product from excessive colouring.
  • the system was placed under vacuum at - 0.5 bar (relative to the atmospheric pressure).
  • ester having formula (Ia) of Example 1 (referred to as 'POLY-GLY-S' for shortness of description) have been investigated in an in vitro inflammation model, on NCTC2544 human keratinocytes and using lipopolysaccharide (LPS) from E. coli as mediator of inflammatory state.
  • LPS lipopolysaccharide
  • the effect of derivative in the models used has been compared to that of 18- ⁇ -glycyrrhetic acid (referred to as '18- ⁇ ' for shortness of description).
  • NCTC2544 human keratinocytes line (Perry V.P. et Al., 1957) has been obtained from the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
  • NCTC 2544 human keratinocytes immortalized line (Perry V.P. et al., 1957) kept in culture in sterile flasks (25 cm 3 ), incubated at 37°C in wet atmosphere at 5% CO 2 in MEM culture medium (Minimum Essential Medium) supplemented with 10% fetal bovine serum (FBS), glutamine 2mM, 1% non essential amino acids, in presence of 1% penicillin and streptomycin.
  • MEM culture medium Minimum Essential Medium
  • FBS fetal bovine serum
  • glutamine 2mM glutamine 2mM
  • non essential amino acids in presence of 1% penicillin and streptomycin.
  • the 1:3 split is carried out every 2 days once the monolayer is reached, by washing with PBS 1X (phosphate buffer without Ca 2+ and Mg 2+ ) and by detaching cells with a solution of tripsin-EDTA at 37°C for 2 minutes.
  • PBS 1X phosphate buffer without Ca 2+ and Mg 2+
  • Negative control NCTC2544 human keratinocytes kept in culture in EMEM (EBSS) at 2.5% FBS, supplemented with L-glutamine 2 mM, 1% amino acid solution and 1% penicillin (10,000 U/ml)/streptomycin (10,000 Ug/ml) mixture at 37°C, 5% CO 2 .
  • the MTT test is useful to assess in vitro cell viability following the treatment with diluted compounds.
  • the MTT method has been used as an indirect measure of cell viability.
  • NCTC 2544 cell proliferation from compounds 18- ⁇ and POLY-GLY-S at different concentrations have been examined.
  • the cells have been plated at low densities and treated with different concentrations of active compounds and negative control, in culture medium EMEM, without phenol red supplemented at 10% with FCS, 2 mM L-glutamine, 1% NEAA solution and 1% antibiotic mixture for 24, 48 and 72 hours and cell viability has been assessed by the MTT assay.
  • the cell viability percentage compared to control ( Figures 1-2 ) has been calculated after 24, 48 and 72 hours of incubation.
  • the test showed that after 24 hours of incubation, none of the 18- ⁇ -glycyrrhetic acid ( Figure 1 ) and of ester having formula (Ia) ( Figure 2 ) concentrations showed a cytotoxic effect on NCTC2544 compared to control.
  • the same results have been obtained after a prolonged cells exposure (48-72 hours) to tested compounds for all the considered concentrations.
  • the expression of the TNF- ⁇ gene on NCTC 2544 cells was assessed by RT-PCR.
  • the gene expression analysis implies four steps:
  • NCTC 2544 human keratinocytes When the cells (NCTC 2544 human keratinocytes) had reached about 80% confluence, they were removed with trypsin / EDTA and seeded at a density of 1 x 10 6 cells/ml in 12-well plates and then incubated at 37°C, 5% CO 2 (24h).
  • POLY-GLY-S and 18- ⁇ were dissolved in EMEN supplemented with 2.5% FBS, 2mM L-glutamine, 1% NEAA solution and 1% penicillin (10,000 U/ml)/streptomycin (10,000 ⁇ g/ml) mixture.
  • each RNA sample was diluted in DEPC water at a final concentration of 2 ⁇ g/ml. This is the concentration required by the reverse transcription kit. An electrophoresis run on gel was also carried out in order to assess the extracted total RNA integrity.
  • the extracted and quantified total RNA was amplified using the "High-Capacity cDNA Reverse transcription Kit” (Applied Biosystems).
  • Random primer were used in order to ensure an effective synthesis of the mRNA first strand.
  • Step 1 Step 2: Step 3: Step 4: Temperature 25°C 37°C 85°C 25°C Time 10 mins 120 mins 60 sec hold
  • samples were diluted with 30 ⁇ l of DEPC water and stored at-20°C until use.
  • RT-PCR was carried out using TaqMan linear probes (Applied Biosystems). These probes are the most used and published detection system for qPCR applications. In stock probes and primer were selected based on previous specific bibliographic studies.
  • the relative quantification method was used where the gene relative concentration of interest (target) is compared with unknown samples to a calibrator or control sample (untreated cells).
  • RT-PCR was carried out using cell treated at different times of treatment and control cells cDNAs. 10 ⁇ l TaqMan 2X Gene Expression master Mix and 1 ⁇ l 20X TaqMan Gene Expression were added to cDNA. Each biological sample was treated in duplicate and amplified as indicated in the table: STEP Step 1: UDG incubation Step 2: Activation of AmpliTaq Gold DNA Polymerase Step 3: PCR Hold Hold Cycle (50 cycles) Denature Anneal/Extend Temperature 50°C 95°C 95°C 60°C Time 2 mins 10 mins 15 sec Hold
  • the resulting comparative quantification is a relative comparative diagram.
  • a value equal to one means no changes in the gene expression of the target gene between the sample being studied and the calibrator, whereas if it is higher it means up-regulation, if lower than one it means down-regulation.
  • a value is significantly regarded as significant if it is higher or lower than once (up-regulated or down-regulated) compared to the calibrator.
  • TNF- ⁇ is typically over expressed in the skin of individuals suffering from psoriasis (Kristensen et al, 1993; Ettehadi et al, 1994) and plays a major role in the pathogenesis of the disease. TNF- ⁇ key role is further supported by both the evidence that in psoriasis other genes regulated by TNF- ⁇ are over expressed and that TNF- ⁇ antagonists are used as highly effective therapeutic agents in most of the patients (Richardson e Gelfand, 2008). Recently, it has been suggested that TNF- ⁇ inhibits barrier proteins expression (for example FLG and LOR), that TNF- ⁇ antagonists may contribute to clinical improvement of patients suffering from psoriasis increasing barrier proteins expression (Kim et al., 2011).
  • barrier proteins expression for example FLG and LOR
  • the validation of the method used was first assessed since it was noted a clear increase of TNF- ⁇ after cell treatment with LPS 5 ⁇ g/ml compared with untreated cells.
  • POLY-GLY-S showed an anti-inflammatory effect on the expression of the TNF- ⁇ gene after 48 hours of incubation. At all the concentrations assayed, POLY-GLY-S was able to reduce the expression of the TNF- ⁇ gene of at least 50% producing an inhibitory effect higher than that produced by 18- ⁇ .

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Claims (10)

  1. Ester d'acide glycyrrhétinique ayant la formule (I) :
    Figure imgb0014
     dans laquelle
    n est un nombre entier de 1 à 3,
    Sorb représente un fragment de sorbitol, et
    Polygly représente un fragment de glycérol ou de polyglycérol.
  2. Ester selon la revendication 1, dans lequel Polygly représente un fragment de polyglycérol présentant un degré de polymérisation de 1,5 à 10.
  3. Ester selon la revendication 2, dans lequel Polygly représente un fragment de polyglycérol présentant un degré de polymérisation de 3 à 5.
  4. Ester selon l'une quelconque des revendications 1 à 3, dans lequel n est 1.
  5. Ester selon la revendication 1 ayant la formule (Ia) :
    Figure imgb0015
  6. Composition cosmétique comprenant au moins un ester selon l'une quelconque des revendications 1 à 5 et au moins un support acceptable sur le plan cosmétique.
  7. Utilisation de l'ester selon l'une quelconque des revendications 1 à 5 comme agent antivieillissement topique dans le traitement cosmétique de la peau, en particulier d'une peau sensible.
  8. Utilisation de l'ester selon l'une quelconque des revendications 1 à 5 comme agent lénitif topique dans le traitement cosmétique de la peau, en particulier d'une peau sensible.
  9. Utilisation de la composition cosmétique selon la revendication 6 pour le traitement cosmétique topique de la peau, en particulier d'une peau sensible.
  10. Procédé de préparation de l'ester d'acide glycyrrhétinique ayant la formule (I), comprenant les étapes suivantes :
    i) la réaction du glycérol ou d'un polyglycérol avec du sorbitol pour donner un éther ; et
    ii) la réaction dudit éther avec de l'acide glycyrrhétinique pour donner l'ester ayant la formule (I).
EP13828837.8A 2012-12-18 2013-12-18 Esters d'acide glycyrrhétinique, leur préparation et leurs applications cosmétiques Active EP2935199B1 (fr)

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IT002169A ITMI20122169A1 (it) 2012-12-18 2012-12-18 Esteri dell'acido glicirretico, loro preparazione e loro applicazioni cosmetiche
PCT/IB2013/061087 WO2014097176A1 (fr) 2012-12-18 2013-12-18 Esters d'acide glycyrrhétinique, leur préparation et leurs applications cosmétiques

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CA (1) CA2895301C (fr)
ES (1) ES2623216T3 (fr)
HU (1) HUE032723T2 (fr)
IT (1) ITMI20122169A1 (fr)
PL (1) PL2935199T3 (fr)
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CN104291477B (zh) * 2014-10-12 2016-06-01 温州志杰机电科技有限公司 一种离合轴焊接头氮化硅锌合金海水脱盐系统
CN112584871A (zh) * 2018-05-01 2021-03-30 希默赛生物技术公司 支化糖醇基化合物和组合物及其方法
IT202200010646A1 (it) * 2022-05-23 2023-11-23 Giuliani Spa Forme di dosaggio per la somministrazione topica di triterpeni pentaciclici

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US3968169A (en) 1973-11-30 1976-07-06 The Procter & Gamble Company Process for preparing polyblycerol
AU2002227308A1 (en) 2000-11-06 2002-05-15 Lonza Inc. Processes for preparing linear polyglycerols and polyglycerol esters
EP1468696A1 (fr) * 2003-04-17 2004-10-20 Boehringer Ingelheim International GmbH Combinaisons d'épinastine et d'agents antiphlogistiques comme nouvelles compositions pharmaceutiques pour le traitement de maladies de la peau
ITMI20080444A1 (it) * 2008-03-17 2009-09-18 Giuliani Spa Agenti per contrastare e ridurre l'azione irritante dei tensioattivi in composizioni da applicare sulla pelle per la cura o la detersione del viso e del corpo

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CA2895301C (fr) 2021-09-21
HUE032723T2 (en) 2017-10-30
EP2935199A1 (fr) 2015-10-28
PL2935199T3 (pl) 2017-08-31
US20150337005A1 (en) 2015-11-26
ITMI20122169A1 (it) 2014-06-19
WO2014097176A1 (fr) 2014-06-26
US9394335B2 (en) 2016-07-19
PT2935199T (pt) 2017-05-17
ES2623216T3 (es) 2017-07-10
CA2895301A1 (fr) 2014-06-26

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